Blood flow patterns switch VEGFR2 activity through differential S-nitrosylation and S-oxidation
Dong Hoon Kang,
Yerin Kim,
Seongchun Min,
Su Youn Lee,
Ka Young Chung,
In-Jeoung Baek,
Kihwan Kwon,
Hanjoong Jo,
Sang Won Kang
Affiliations
Dong Hoon Kang
Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea
Yerin Kim
Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea
Seongchun Min
Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea
Su Youn Lee
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
Ka Young Chung
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
In-Jeoung Baek
Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
Kihwan Kwon
Department of Cardiology, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
Hanjoong Jo
Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA 30322, USA
Sang Won Kang
Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea; Corresponding author
Summary: Vascular endothelial growth factor receptor-2 (VEGFR2) plays a key role in maintaining vascular endothelial homeostasis. Here, we show that blood flows determine activation and inactivation of VEGFR2 through selective cysteine modifications. VEGFR2 activation is regulated by reversible oxidation at Cys1206 residue. H2O2-mediated VEGFR2 oxidation is induced by oscillatory flow in vascular endothelial cells through the induction of NADPH oxidase-4 expression. In contrast, laminar flow induces the expression of endothelial nitric oxide synthase and results in the S-nitrosylation of VEGFR2 at Cys1206, which counteracts the oxidative inactivation. The shear stress model study reveals that disturbed blood flow operated by partial ligation in the carotid arteries induces endothelial damage and intimal hyperplasia in control mice but not in knock-in mice harboring the oxidation-resistant mutant (C1206S) of VEGFR2. Thus, our findings reveal that flow-dependent redox regulation of the VEGFR2 kinase is critical for the structural and functional integrity of the arterial endothelium.
